Variably protease-sensitive prionopathy in the context of a complex proteinopathy: clinical and neuropathological challenges

Variably protease-sensitive prionopathy (VPSPr) is the most recently identified sporadic human prion disease, displaying distinctive clinical and neuropathological features and a unique western blot profile. Clinically, it frequently presents with longer disease duration than classic sporadic Creutzfeldt-Jakob disease (sCJD), neuropathologically with characteristic prion protein (PrP) deposition patterns, and biochemically with variable resistance of PrP Sc to proteinase K (PK) digestion. Here, we describe clinico-pathological features of two new patients with VPSPr identified at postmortem examination, review current literature, and emphasize diagnostic challenges when combined with other neurodegenerative conditions. As in sCJD, the polymorphism M/V at codon 129 of the PRNP gene influences the phenotypic expression, which includes features within the frontotemporal lobar degeneration and motor neuron disease (FTLD-MND) spectrum. Genetic and molecular analysis, as well as postmortem neuropathological examination and western blotting (case 2) were performed. Case 1 with an MM genotype showed a prominent involvement of the motor cortex and striatum, consistent with the pyramidal and extrapyramidal clinical symptoms. The cerebellum was devoid of PrP deposits. Co-pathologies including tau pathology consistent with argyrophilic grain disease (AGD) and limbic-predominant age-related TDP-43 encephalopathy (LATE) were detected as well. Case 2 with a VV genotype displayed a prominent involvement of the cerebellum with microplaques and a slightly different PrP staining pattern, compared to case 1. Both patients showed a prolonged disease duration, 7 years and 3.5 years, respectively. The clinical and neuropathological diagnosis of VPSPr remains challenging, especially in the presence of co-pathologies. The codon 129 M/V polymorphism modulates the clinic and/or pathological phenotypic expression of VPSPr within the FT(L)D-MND spectrum.